This is an application for a Mentored Patient-Oriented Career Development Award (K23). This award will provide the Applicant with advanced skills needed to establish an independent program of research in obesity and metabolic dysfunction using neuroimaging and neuropsychological methodologies. The proposed study will use fMRI, biomarkers of metabolic functioning, and neuropsychological tests to examine changes in cognition and brain response in obese and sedentary middle aged adults undergoing treatment for insulin resistance. We will enroll 75 obese participants who are participating in an existing study of weight reduction at the Nutrition and Obesity Research Center at Washington University Medical School. The participants will be randomly assigned to one of three conditions: 1) Six months of treatment with an oral thiazolidinedione medication (pioglitazone) to increase insulin sensitivity (n=25); 2) Six months of a standardized weight reduction intervention to achieve an 8-10% weight reduction and increased insulin sensitivity (n=25); or 3) A wait-list control group following 6 months of usual diet and weight maintenance (n=25). At baseline and follow- up, all participants will complete glucose clamp testing, body composition assessment, blood tests, blood pressure checks, comprehensive psychometric assessment, brief psychiatric assessment, physical activity questionnaires, and structural and functional MRI. The aims of the study are: 1) To determine if neuropsychological performance will improve as a function of increased insulin sensitivity and 2) To determine whether improved sensitivity to insulin will result in increased neural efficiency as measured by fMRI brain response. The Applicant proposes a comprehensive training plan, combining didactic instruction with established researchers; formal coursework including completion of a Master's Degree in Clinical Investigation; participation in several advanced workshops; participation in ongoing seminars at Washington University Medical School including the Nutrition and Obesity Research Seminar, the Knight Alzheimer's Disease Research Center; and applied training experiences with individual mentors. Specific training goals include advanced knowledge and skill acquisition in neuroimaging methodologies, including task-based fMRI, longitudinal approaches in fMRI, and structural MRI cortical reconstruction techniques. Training in advanced statistical modeling methodologies will also be provided by coursework and workshop participation. Additional coursework will be completed in nutrition, metabolism, endocrinology, multimodal neuroimaging, and the responsible conduct of research. The overall research goal of this proposal is to test the hypothesis that improved insulin sensitivity achieved through weight reduction or thiazolidinedione treatment is accompanied by beneficial changes in cognitive performance and fMRI brain response. PUBLIC HEALTH RELEVANCE: Brain functioning is an important determinant of health outcomes and quality of life, and given the scope of the obesity epidemic in the United States, consideration of treatment effects on brain functioning are essential as the obese population ages. Providing evidence of specific mechanisms that promote improved cognitive abilities and brain heath may help clinicians emphasize behaviors and treatment strategies that reduce risk of more serious disease as patients advance in age.